Year: 2014
Type: dissertation
Abstract: Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system classically discussed as an autoimmune disease. However, recent neuropathological evidence suggests that primary oligodendrogliopathy might trigger the inflammatory response during MS lesion development. In my thesis I showed that cuprizone-treatment induced a distal oligodendrogliopathy within days that was paralleled by early microgliosis. The chemokines CXCL10, CCL2 and CCL3 were found to be upregulated in this tissue. In CXCL10, but not CCL2 and CCL3 deficient mice, microglia recruitment was decreased indicating a pivotal role of CXCL10 in the initiation of inflammatory foci. CXCL10 was found to be predominantly expressed by damaged oligodendrocytes. Further in vitro studies confirmed that oligodendrocyte-derived CXCL10 induced microglia migration and a pro-inflammatory M1-phenotype. In summary, my results show that stressed oligodendrocytes release CXCL10, which activates microglia suggesting that oligodendrocytes can actively participate in the initiation of neuroinflammatory events. In the second part of my thesis I investigated the role of the growth factors FGF-2 and PDGFalpha on oligodendrocyte precursor cell (OPC) maturation, a process necessary to achieve correct and sufficient remyelination in MS lesions. FGF-2 and PDGFalpha treatment of primary OPCs showed that both growth factors negatively influence maturation of oligodendrocytes in vitro. An imbalance in this growth factor system might thus account for some aspects of oligodendrocyte pathology observed in distinct MS lesion subtypes and remyelination failure. In the last part of my thesis I investigated redundant functions of the chemokines CCL2 and CCL3 using a newly bred double knockout mouse strain (CCL2/3-/-) deficient in both genes. A basic investigation of the mice confirmed the absence of CCL2 and CCL3 on the mRNA and protein level and revealed that the mice show no gross abnormalities in brain tissue morphology and histology. Interestingly, a 5 weeks cuprizone-trial showed that CCL2/3-/- mice display regional differences with less severe demyelination, oligodendrocyte loss and astroglia activation in the cortex, but not in the corpus callosum compared to wild type mice. With respect to MS pathology, future studies have to take into consideration that white and gray matter display different regions with respect to their cytoarchitecture and molecular composition.
Source: RWTH Publications (RWTH Aachen)
Authors: K Janssen, Cordian Beyer
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W593341567